Hybrid cross-linking characteristics of hydrogel control stem cell fate

Controlling hydrogel structures by combination of physical and chemical cross-links provides a novel system to regulate (stem) cell fate. In this study, we designed a polyethylene glycol (PEG)-based hydrogel where the polymer chains contain both physical and chemical cross-linking units in the same chain with self-assembling L-tyrosine-based dipeptides and photopolymerizable polyacrylate groups, respectively. It is shown that hydrogel architectures derived from this polymer are correlated to the cross-linking mechanisms. Combination of these cross-links controls three-dimensional gel architecture to regulate stem cell behavior in these hydrogels. Particularly, interaction of mesenchymal stem cells with the hydrogel enabled cellular aggregation to enhance chondrogenic differentiation as observed from the deposition of chondrogenic matrix. Increased chondrogenesis was due to enhanced cell-cell adhesion, which was mediated by gel morphology. This study shows the interplay of physical and chemical cross-links in hydrogels to regulate stem cell function and provides a novel molecular engineering tool for controlling hydrogel properties.